Abstract
Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
Highlights
Elie Metchnikoff discovered macrophages in 1882 when he observed that, following injury, certain specialized cells of the starfish larva would surround and phagocytose foreign material
SMAD4 signaling is downstream of the Bone morphogenic protein (BMP) signals identified as essential for Kupffer cell (KC) differentiation by Bonnardel et al Collectively, these results suggest a model where DLL1 and DLL4 on Liver sinusoidal endothelial cells (LSEC) induce rapid activation of a poised enhancer landscape in monocytes, leading to the rapid increase in expression of KC Lineage determining transcription factor (LDTF) such as liver x receptor a (LXRa) and SPIC
KCs express scavenger receptors and Transcription factor (TF) involved in lipid metabolism and homeostasis as well as a variety of TFs involved in sensing and responding to pathogenic material found in portal blood
Summary
Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis
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